Ring fused pyrazole derivatives as CRF antagonists

ABSTRACT

This invention relates to compounds which are generally CRF-1 receptor antagonists and which are represented by Formula I or Formula II: 
                         
wherein Ar is optionally substituted aryl or heteroaryl, R 1 –R 4  are as defined in the specification; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof. The invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing such compounds, and to methods for their use as therapeutic agents.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a divisional application of U.S. Ser. No 10/308,386,filed Dec. 3, 2002, now U.S. Pat. No. 6,821,984, which claims benefitunder Title 35 U.S.C. 119(e) of U.S. Provisional Applications Nos.60/336,751 filed Dec. 4, 2001; and 60/408,613 filed Sep. 6, 2002, allapplications are hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to ring fused pyrazole derivatives with CRFactivity, and associated pharmaceutical compositions, and methods foruse as therapeutic agents.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF) or hormone (CRH) is one of severalneurohormones synthesized by specific hypothalamic nuclei in the brainwhere it activates the transcription of the pro-opiomelanocortin (POMC)gene resulting in release of adrenocorticotropic hormone (ACTH) andbeta-endorphin from anterior pituitary cells (Vale et al, Science 213,1394–1397 (1981)). The fundamental role of CRF is to prepare theorganism for an appropriate response to various stressors such asphysical trauma, insults of the immune system and social interactions.CRF also has CNS effects by acting at higher centers in the brain,particularly cortical regions where there is a widespread distributionof CRF neurons. CRF is believed to be a key intermediary incommunication between the immune, central nervous, endocrine andcardiovascular systems (Sapolsky et al, Science 238, 522–524 (1987)).The role played by CRF in integrating the response of the immune systemto physiological, psychological and immunological stressors has beendescribed in the art, e.g. J. E. Blalock, Physiological Reviews 69, 1(1989) and J. E. Morley, Life Sci. 41, 527 (1987).

CRF antagonists are effective in the treatment of a wide range ofstress-related illnesses, mood disorders such as depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,bipolar disorder and cyclothymia; chronic fatigue syndrome; eatingdisorders such as obesity, anorexia and bulimia nervosa; generalizedanxiety disorder; panic disorder; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; pain perception such asfibromyalgia; headache; stress-induced gastrointestinal dysfunction suchas irritable bowel syndrome (IBS), colonic hypersensitivity or spasticcolon; hemorrhagic stress; ulcers; stress-induced psychotic episodes;inflammatory disorders such as rheumatoid arthritis and osteoarthritis;asthma; psoriasis; allergies; premature birth; hypertension; congestiveheart failure; sleep disorders; neurodegenerative diseases such asAlzheimer's disease, senile dementia, Parkinson's disease andHuntington's disease; head or spinal cord trauma; ischemic neuronaldamage; excitotoxic neuronal damage; epilepsy; stroke; psychosocialdwarfism; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms;,stress-induced immune dysfunctions; immunesuppression and stress-induced infections; cardiovascular or heartrelated diseases; fertility problems; and/or human immunodeficiencyvirus infections. Accordingly clinical data suggests that CRF receptorantagonists may represent novel antidepressants and/or anxiolytic drugsthat may be useful in the treatment of the neuropsychiatric disordersmanifesting hypersecretion of CRF.

In view of the above, efficacious and specific antagonists of CRF aredesired as potentially valuable therapeutic agents for the treatment ofpsychiatric disorders and neurological diseases. It is thus desirable todiscover new CRF antagonists.

All publications, patents, and patent applications cited herein, whethersupra or infra, are each hereby incorporated by reference in itsentirety.

SUMMARY OF THE INVENTION

This invention relates to compounds comprising Formula I or Formula II:

wherein:

R¹ is —OR^(a), —NR^(a)R^(b), —CR^(c)R^(d)R^(e), CO₂R^(a), or—C(O)NR^(a)R^(b); or R¹ is hydrogen, halogen, cycloalkenyl, aryl, orheteroaryl, where each aryl or heteroaryl is optionally substituted withone or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano,nitro, —C(O)NR^(a′)R^(b′), and —NR^(a′)R^(b′), where R^(a′) and R^(b′)are each independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl;

R² is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl,C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, aryl, or arylalkyl, wherein saidaryl or arylalkyl is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, haloalkyl,C₁₋₆alkoxy, and halogen;

R³ and R⁴ are each independently selected from hydrogen and C₁₋₆alkyl,or R³ and R⁴ are taken together with the carbon, to which they areattached to form a C₃₋₆cycloalkyl ring;

Ar is aryl or heteroaryl, each optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl;

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, carboxyalkyl, C₁₋₆alkoxycarbonyl,C₁₋₆-alkoxy-C₁₋₃alkylcarbonyl, acyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, di-C₃₋₆cycloalkylC₁₋₃alkyl, C₁₋₆heteroalkyl,aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C₅₋₈heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,phenylalkyl, diphenylalkyl, phenylsulfonyl optionally substituted asdescribed for phenyl below, and C₁₋₃alkyl substituted with both aC₃₋₆cycloalkyl and a phenyl group, wherein each of said cycloalkyl,phenyl, aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl; or

R^(a) and R^(b) are taken together with the nitrogen to which they areattached form an heterocyclyl or heteroaryl ring selected from the groupconsisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group;

R^(c) is hydrogen, hydroxy, C₁₋₆alkoxy, or —NR^(a″′)R^(b″′);

R^(d) and R^(e) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, di-C₃₋₆cycloalkyl-C₁₋₃alkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C₁₋₃alkyl,and C₁₋₃alkyl substituted with both a C₃₋₆cycloalkyl and a phenyl group,wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,amino, alkylamino, dialkylamino, and halogen; or

R^(c) and R^(d) are taken together to form a divalent group selectedfrom C₁₋₆alkylidenyl, C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl,C₃₋₆cycloalkyl-alkylidenyl, C₃₋₆Cycloalkylalkyl-alkylidenyl,C₃₋₆heterocyclylidenyl, C₃₋₆heterocyclyl-C₁₋₃alkylidenyl,C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkyl-alkylidenyl, heteroaryl-C₁₋₃alkylidenyl, andheteroarylalkyl-C₁₋₃alkylidenyl, wherein each of said cycloalkyl, aryl,or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, haloalkyl,C₁₋₆alkoxy, amino, alkylamino, dialkylamino, and halogen; or

R^(d) and R^(e) are taken together with the carbon to which they areattached to form a cycloalkyl or heterocyclyl ring;

R^(a″′) and R^(b″′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl, carboxyalkyl, C₁₋₆alkoxycarbonyl,C₁₋₆-alkoxy-C₁₋₃alkylcarbonyl, acyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, di-C₃₋₆cycloalkyl-C₁₋₃alkyl, C₁₋₆heteroalkyl,aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C₅₋₈heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,phenylalkyl, diphenyl-C₁₋₃alkyl, and C₁₋₃alkyl substituted with both aC₃₋₆cycloalkyl and a phenyl group, wherein each of said cycloalkyl,phenyl, aryl, or heteroaryl groups is optionally substituted with one ormore substituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl; or

R^(a″′) and R^(b″′) are taken together with the nitrogen to which theyare attached form an heterocyclyl or heteroaryl ring selected from thegroup consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline,pyrrole, pyrazole, and imidazole, where each of said rings is optionallysubstituted with one or more substituents selected from the groupconsisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl,aminocarbonylamino, aminosulfonyl, alkylsulfonylamino,aminosulfonylamino, and phenyl, wherein each of said phenyl groups isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,and halogen, and each of said amino groups is optionally monosubstitutedor disubstituted with alkyl, or is contained in a pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl group;

n is an integer selected from 0, 1 and 2;

a is a single or double bond;

providing that when n is 0, R¹ is not hydrogen; when n is 0 and a is adouble bond, R⁴ is absent; and when n is 1 or 2, a is a single bond;

or individual isomers, racemic or non-racemic mixtures of isomers, orpharmaceutically acceptable salts or solvates thereof.

In one embodiment, a compound of Formula I is described:

wherein R¹, R², R³, R⁴, Ar, a, and n are as defined above.

In another embodiment, compounds of Formula III are described:

wherein the integer n is 1 or 2, and R¹, R², R³, R⁴, and Ar are asdefined above.

In another embodiment, compounds of Formula III are described, whereinAr is a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, and R¹, R², R³, and R⁴are as defined above.

In one aspect, such compounds are described wherein R³ and R⁴ are eachindependently selected from hydrogen and methyl.

In another aspect, such compounds are described wherein Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

In another aspect, such compounds are described wherein Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare each independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, halogen, haloalkyl, cyano, alkylamino,dialkylamino, and nitro.

In another aspect, such compounds are described wherein R² is hydrogen,C₁₋₆alkyl, or C₁₋₆alkylcarbonyl.

In another embodiment, compounds of Formula IV are described:

wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, andthe substituents are each independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, halogen, haloalkyl,cyano, alkylamino, dialkylamino, and nitro, R² is hydrogen, C₁₋₆alkyl,or C₁₋₆alkylcarbonyl, R³ and R⁴ are each independently selected fromhydrogen and methyl; and R¹ is as defined above.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydroxy; and R^(d) and R^(e) are asdefined above.

In one aspect, such compounds are described wherein R^(d) and R^(e) areeach independently selected from the group consisting of hydrogen,C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

In one alternative, such compounds are described wherein R^(d) and R^(e)are each independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

In another aspect, such compounds are described wherein R² is C₁₋₆alkyl;R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are each independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

In another alternative, such compounds are described wherein R^(d) andR^(e) are taken together to form a cycloalkyl or heterocyclyl group.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) aretaken together to form a divalent group selected from C₁₋₆alkylidenyl,C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen.

In one alternative, such compounds are described wherein R^(c) and R^(d)are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where the heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen; and R^(c) and R^(d) are taken together to form a divalentgroup selected from C₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl, or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, amino, alkylamino,and dialkylamino.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydrogen; and R^(d) and R^(e) are asdefined above.

In one aspect, such compounds are described wherein R^(d) and R^(e) areeach independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, where each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen.

In one alternative, such compounds are described wherein R^(d) and R^(e)are each independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; R² is C₁₋₆alkyl; R³ andR⁴ are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstitutedphenyl, and the substituents are independently selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, cyano, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —NR^(a)R^(b); —C(O)NR^(a)R^(b); or —CR^(c)R^(d)R^(e), where R^(c)is —NR^(a″′)R^(b″′); R^(d) and R^(e) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl; and R^(a), R^(b),R^(a″′), and R^(b″′)are as defined above.

In one aspect, such compounds are described wherein R^(a), R^(b),R^(a″′), and R^(b″′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl,wherein each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

In one alternative, such compounds are described wherein R^(a) andR^(b), or R^(a″′) and R^(b″′), are taken together with the nitrogen towhich they are attached form an heterocyclyl ring selected from thegroup consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, andimidazoline, where each of said rings is optionally substituted with oneor more substituents independently selected from the group consisting ofhydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl,aminocarbonylalkyl, and aminocarbonylamino, and each of said aminogroups is optionally monosubstituted or disubstituted with alkyl, or iscontained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinylgroup.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —NR^(a)R^(b); R^(a) is selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b) is selected from thegroup consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

In one aspect, such compounds are described wherein R² is C₁₋₆alkyl; R³and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is —NR^(a″′)R^(b″′); R^(d) and R^(e) areeach independently selected from the group consisting of hydrogen andC₁₋₉alkyl; R^(a″′) is selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b″′) is selected from the groupconsisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

In one aspect, such compounds are described wherein R² is C₁₋₆alkyl; R³and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —OR^(a), and R^(a) is as defined above.

In one aspect, such compounds are described wherein R^(a) is selectedfrom the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofsaid cycloalkyl, aryl, or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

In another aspect, such compounds are described wherein R² is C₁₋₆alkyl;R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen andC₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted phenyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is aryl or heteroaryl, where said aryl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen,haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) areeach independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

In one alternative, such compounds are described wherein the aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,cyano, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

In another embodiment, compounds of Formula III are described, whereinAr is a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, and R¹, R², R³, and R⁴are as defined above.

In one aspect, such compounds are described wherein R³ and R⁴ are eachindependently selected from hydrogen and methyl.

In another aspect, such compounds are described wherein Ar is a2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

In another aspect, such compounds are described wherein Ar is a2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,alkylamino, and dialkylamino.

In another aspect, such compounds are described wherein R² is hydrogen,C₁₋₆alkyl, or C₁₋₆alkylcarbonyl.

In another embodiment, compounds of Formula IV are described wherein Aris a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstitutedpyridin-3-yl, and the substituents are each independently selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,alkylamino, and dialkylamino, R² is hydrogen, C₁₋₆alkyl, orC₁₋₆alkylcarbonyl, R³ and R⁴ are each independently selected fromhydrogen and methyl; and R¹ is as defined above.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydroxy; and R^(d) and R^(e) are asdefined above.

In one aspect, such compounds are described wherein R^(d) and R^(e) areeach independently selected from the group consisting of hydrogen,C₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

In one alternative, such compounds are described wherein R^(d) and R^(e)are each independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen.

In another aspect, such compounds are described wherein R² is C₁₋₆alkyl;R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are each independently selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

In another alternative, such compounds are described wherein R^(d) andR^(e) are taken together to form a cycloalkyl or heterocyclyl group.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; and R^(c) and R^(d) aretaken together to form a divalent group selected from C₁₋₆alkylidenyl,C₁₋₆heteroalkylidenyl, C₃₋₆cycloalkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆cycloalkylalkyl-alkylidenyl, C₃₋₆heterocyclylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, C₃₋₆heterocyclylalkyl-C₁₋₃alkylidenyl,aryl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkyl-alkylidenyl,heteroaryl-C₁₋₃alkylidenyl, and heteroarylalkyl-C₁₋₃alkylidenyl, whereineach of said cycloalkyl, aryl, or heteroaryl groups is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino, andhalogen.

In one alternative, such compounds are described wherein R^(c) and R^(d)are taken together to form a divalent group selected fromC₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl, aryl-C₁₋₃alkylidenyl, andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino,alkylamino, dialkylamino, and halogen.

In another embodiment, compounds, of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(e) is selected from the group consisting ofC₁₋₉alkyl, C₁₋₆alkoxyalkyl, and heteroaryl, where the heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy,and halogen; and R^(c) and R^(d) are taken together to form a divalentgroup selected from C₁₋₆alkylidenyl, C₃₋₆cycloalkyl-alkylidenyl,C₃₋₆heterocyclyl-C₁₋₃alkylidenyl, aryl-C₁₋₃alkylidenyl andheteroaryl-C₁₋₃alkylidenyl, wherein each of said aryl, or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, amino, alkylamino,and dialkylamino.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is hydrogen; and R^(d) and R^(e) are asdefined above.

In one aspect, such compounds are described wherein R^(d) and R^(e) areeach independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, where each of said aryl or heteroarylgroups is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen.

In one alternative, such compounds are described wherein R^(d) and R^(e)are each independently selected from the group consisting of C₁₋₉alkyl,C₁₋₆alkoxyalkyl, aryl, and heteroaryl, where each of said aryl orheteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, and halogen; R² is C₁₋₆alkyl; R³ andR⁴ are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or2,4,6-trisubstituted pyridin-3-yl, and the substituents areindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), where R^(a″) andR^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —NR^(a)R^(b); —C(O)NR^(a)R^(b); or —CR^(c)R^(d)R^(e), where R^(c)is —NR^(a″′)R^(b″′); R^(d) and R^(e) are each independently selectedfrom the group consisting of hydrogen and C₁₋₉alkyl; and R^(a), R^(b),R^(a″′), and R^(b″′) are as defined above.

In one alternative, such compounds are described wherein R^(a), R^(b),R^(a″′), and R^(b″′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl,wherein each of said aryl or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

In another alternative, such compounds are described wherein R^(a) andR^(b), or R^(a″′) and R^(b″′), are taken together with the nitrogen towhich they are attached form an heterocyclyl ring selected from thegroup consisting of pyrrolidine, piperidine, homopiperidine,tetrahydropyridine, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine,hexahydropyrimidine, pyrazolidine, piperazine, morpholine, andimidazoline, where each of said rings is optionally substituted with oneor more substituents independently selected from the group consisting ofhydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl,aminocarbonylalkyl, and aminocarbonylamino, and each of said aminogroups is optionally monosubstituted or disubstituted with alkyl, or iscontained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinylgroup.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —NR^(a)R^(b); R^(a) is selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b) is selected from thegroup consisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

In one alternative, such compounds are described, wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —CR^(c)R^(d)R^(e); R^(c) is —NR^(a″′)R^(b″′); R^(d) and R^(e) areeach independently selected from the group consisting of hydrogen andC₁₋₉alkyl; R^(a″′) is selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₆alkoxyalkyl; and R^(b″′) is selected from the groupconsisting of C₁₋₉alkyl, hydroxyalkyl, C₁₋₆alkoxyalkyl,heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of saidaryl or heteroaryl groups is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino, dialkylamino,hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, andhalogen, and each of said amino groups is optionally monosubstituted ordisubstituted with alkyl.

In one alternative, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is —OR^(a), and R^(a) is as defined above.

In one alternative, such compounds are described wherein R^(a) isselected from the group consisting of C₁₋₉alkyl, C₁₋₆alkoxyalkyl,C₃₋₆cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each ofsaid cycloalkyl, aryl, or heteroaryl groups is optionally substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₆alkyl, haloalkyl, C₁₋₆alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl,alkylsulfonyloxy, and halogen, and each of said amino groups isoptionally monosubstituted or disubstituted with alkyl.

In another alternative, such compounds are described wherein R² isC₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a 2,4-disubstituted,2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and thesubstituents are independently selected from the group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl, and —NR^(a″)R^(b″), whereR^(a″) and R^(b″) are each independently selected from the groupconsisting of hydrogen and C₁₋₉alkyl.

In another embodiment, compounds of Formula III are described, whereinR³ and R⁴ are each independently selected from hydrogen and methyl, Aris a di- or tri-substituted pyridinyl, and the substituents are eachindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl, the integer n is 1 or 2, R² is as defined above;and

R¹ is aryl or heteroaryl, where said aryl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, halogen,haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) areeach independently selected from the group consisting of hydrogen,C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

In one alternative, such compounds are described wherein the aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloalkyl,cyano, and —NR^(a′)R^(b′), where R^(a′) and R^(b′) are eachindependently selected from the group consisting of hydrogen, C₁₋₉alkyl,and C₁₋₉alkylcarbonyl.

The invention further relates to pharmaceutical compositions containinga therapeutically effective amount of at least one compound of Formula Ior Formula II, or individual isomers, racemic or non-racemic mixtures ofisomers, or pharmaceutically acceptable salts or solvates thereof, inadmixture with at least one suitable carrier.

The invention further relates to a method of treating a subject that hasa disease state that is alleviated by treatment with a CRF receptorantagonist, wherein said method comprises administering to said subjecta therapeutically effective amount of the compound of Formula I orFormula II.

In one embodiment, a method of treating a subject that has a diseasestate comprising disorders of the CNS is described herein. In anotherembodiment, a method of treating a subject with a disease statecomprising phobias, stress related illnesses, mood disorders, eatingdisorders, generalized anxiety disorders, stress inducedgastrointestinal dysfunctions, neurodegenerative diseases, orneuropsychiatric disorders is described herein.

The invention further relates to a process for preparing a compound ofFormula I, where a is a single bond, comprising:

(a) treating a compound of formula:

where R³, R⁴, and Ar are as defined in claim 1, with a compound offormula:

where R is alkyl, to form a first intermediate of formula:

(b) treating the first intermediate with a compound of formula:R²—NHNH₂,where R² is as defined in claim 1, to form a second intermediate offormula:

In one embodiment, the process further comprises (c) treating the secondintermediate with a compound of formula:R^(a)—OH,where R^(a) is as defined in claim 1, to form a compound of Formula I,wherein R¹ is —OR^(a).

In one alternative, the process further comprises (c) treating thesecond intermediate with a brominating reagent to form a thirdintermediate of formula:

In another embodiment, the process further comprises (d) converting thethird intermediate into an anion of formula:

and

-   -   (e) treating the anion with a compound of formula:

where Rd and Re are as defined in claim 1, to form a compound of FormulaI, wherein R¹ is —CR^(c)R^(d)R^(e), and R^(c) is hydroxy.

In one alternative, the process, further comprises (e) treating theanion with a compound of formula:C(O)₂,to form a compound of Formula I, wherein R¹ is —CO₂R^(a).

In another embodiment, the process further comprises (d) treating thethird intermediate with a compound of formula:

where Ar′ is aryl or heteroaryl, where each aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxyl C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′), where R^(a′) andR^(b′) are each independently selected from the group consisting ofhydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl, to form a compound ofFormula I, wherein R¹ is aryl or heteroaryl, where each aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and —NR^(a′)R^(b′),where R^(a′) and R^(b′) are each independently selected from the groupconsisting of hydrogen, C₁₋₉alkyl, and C₁₋₉alkylcarbonyl.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” or “lower alkyl” means a monovalent linear or branched saturatedhydrocarbon radical, consisting solely of carbon and hydrogen atoms,having from one to six carbon atoms inclusive, unless otherwiseindicated. Examples of alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl, n-hexyl, and the like.

“Alkylene” means a divalent linear or branched saturated hydrocarbonradical consisting solely of carbon and hydrogen atoms, having from oneto six carbon atoms inclusive, unless otherwise indicated. Examples ofalkylene radicals include, but are not limited to, methylene, ethylene,propylene, 2-methylethylene, 3-methylpropylene, 2-ethylethylene,pentylene, hexylene, and the like

“Alkoxy” means a radical —OR, wherein R is a lower alkyl radical asdefined herein. Examples of alkoxy radicals include, but are not limitedto, methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” denotes one or more alkoxy group(s) as defined above whichis (are) bonded to an alkyl group as defined above. Examples aremethoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl,ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl,propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl,ethoxypentyl, propyloxypentyl,1,4-dimethoxypropyl, including theirisomers. C₁₋₆ alkoxyalkyl denotes a group wherein the alkyl portion iscomprised of 1–6 carbon atoms exclusive of carbon atoms in the alkoxyportion of the group.

“Cycloalkyl” means a monovalent saturated carbocyclic radical consistingof one or more rings, which can optionally be substituted with hydroxy,cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino,aminocarbonyl, carbonylamino, aminosulfonyl, and sulfonylamino, unlessotherwise indicated. Examples of cycloalkyl radicals include, but arenot limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl,cycloheptyl, and the like.

“Cycloalkylalkyl” means a radical —R′R″, wherein R′ is an alkyleneradical, and R″ is a cycloalkyl radical as defined herein. Examples ofcycloalkylalkyl radicals include, but are not limited to,cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.

“Cycloalkenyl” means a monovalent unsaturated carbocyclic radicalconsisting of one or more rings, which can optionally be substitutedwith hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, andsulfonylamino, unless otherwise indicated. Examples of cycloalkenylradicals include, but are not limited to, cyclobuten-1-yl,3-ethylcyclobuten-1-yl, cyclopenten-1-yl, 3-fluorocyclohepten-1-yl, andthe like.

“Halogen” or “halo” means the radical fluoro, bromo, chloro, or iodo,and combinations thereof.

“Haloalkyl” means a lower alkyl radical as defined herein substituted inany position with one or more halogen atoms as defined herein. Examplesof haloalkyl radicals include, but are not limited to,1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

“Aryl” means a monocyclic or bicyclic radical of 6 to 12 ring carbonatoms having at least one aromatic ring, with the understanding that theattachment point of the aryl radical will be on an aromatic ring. Thearyl radical is optionally substituted independently with one or moresubstituents, preferably one to three substituents, selected from alkyl,haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino,alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylsulfonyloxy, —SO2NR′R″ (where R′ and R″ are independently hydrogenor alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo,nitro, cyano, thio, methylenedioxy or ethylenedioxy. More specificallythe term aryl includes, but is not limited to, phenyl, naphthyl,tetrahydronaphthyl, 3,4-methylenedioxyphenyl,1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinoline-7-yl,and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from nitrogen, oxygen, and sulfur, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic ring.The heteroaryl ring is optionally substituted independently with one ormore substituents, preferably one or two substituents, selected fromalkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino,alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylsulfonyloxy, —SO₂NR′R″ (where R′ and R″ are independently hydrogenor alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo,nitro, cyano, thio, methylenedioxy or ethylenedioxy. More specificallythe term heteroaryl refers to monocyclic aromatic moieties having 5 to 6ring atoms, including 1 to 2 heteroatoms, and includes, but is notlimited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl,triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, and pyrimidinyl,and derivatives thereof. In addition, the term heteroaryl refers tobicyclic aromatic moieties having 9 to 10 ring atoms, including 1 to 3heteroatoms, and includes, but is not limited to, benzofuranyl,tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolinyl, 5,6,7,8-tetrahydroquinolinyl, isoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, benzimidazolyl, benzisoxazolyl, andbenzothienyl, and derivatives thereof.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, two,or three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; and R^(b) and R^(c) areindependently selected from the group consisting of hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) ishydrogen, alkyl, cycloalkyl, and cycloalkylalkyl. When n is 1 or 2,R^(d) is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino,monoalkylamino, or dialkylamino. Representative examples include, butare not limited to, 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl,aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl,methylaminosulfonylmethyl, methylaminosulfonylethyl,methylaminosulfonylpropyl, and the like.

“Heterocyclyl” means a saturated or unsaturated non-aromatic monocyclicor bicylic radical of 3 to 10 ring atoms in which one or two ring atomsare heteroatom containing groups selected from NR′, O, or S(O)_(n)(where R′ is alkyl, heteroalkyl, or hydrogen, and n is an integer from 0to 2), the remaining ring atoms being carbon. The heterocyclyl radicalis optionally substituted with one or more substituents selected fromthe group consisting of hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl,heteroalkyl, and acyl. The term heterocyclyl includes, but is notlimited to, tetrahydropyranyl, piperidino, tetrahydropyrimidin-5-yl,tetrahydropyrimidin-1-yl, N-methylpiperidin-3-yl, piperazino,N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino,thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, pyrrolinyl,imidazolinyl, tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl,and the like.

“Arylalkyl” means a radical —R′R″ where R′ is an alkylene radical and R″is an aryl radical as defined herein. Examples of arylalkyl radicalsinclude, but are not limited to, 4-fluorophenylmethyl,3,4-dichlorophenylethyl, and the like.

“Heteroarylalkyl” means a radical —R′R″ where R′ is an alkylene radicaland R″ is an heteroaryl radical as defined herein. Examples ofheteroarylalkyl radicals include, but are not limited to, such as3-pyridinylmethyl, 4-chloropyrimidin-2-ylmethyl, 2-thiophen-2-ylethyl,and the like.

“Heterocyclylalkyl” means a radical —R′R″ where R′ is an alkyleneradical and R″ is an heterocyclyl radical as defined herein. Examples ofheterocyclylalkyl radicals include, but are not limited to,tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl, 3-piperidinylmethyl,morpholin-1-ylpropyl, and the like.

“Alkylamino” means a radical —NR′R″, wherein R′ is hydrogen or alkyl,and R″ is an alkyl radical as defined herein. Examples of alkylaminoradicals include, but are not limited to, methylamino, ethylamino,cyclopropylmethylamino, dicyclopropylmethylamino, dimethylamino,methylethylamino, diethylamino, di(1-methylethyl)amino, and the like.

“Acyl” means a formyl radical of the formula —C(O)H, or a carbonylradical of the formula —C(O)R′, where R′ is selected from the groupconsisting of C₁₋₁₈alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heteroalkyl, heterocyclyl, heterocyclylalklyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or amino, as definedherein, where said amino is optionally monosubstituted or disubstitutedwith alkyl, or said amino is contained in a pyrrolidinyl, piperidinyl,morpholinyl, or piperazinyl group.

“Alkylidenyl” means a bivalent radical ═CRR′, wherein R and R′ areindependently an alkyl radical or hydrogen, as defined herein. Examplesof alkylidenyl radicals include, but are not limited to, ethylidenyl,propylidenyl, butylidenyl, and the like.

“Cycloalkylidenyl” means a bivalent radical ═CRR′, wherein R and R′ aretaken together with the carbon to which they are attached to form abivalent cycloalkyl radical, as defined herein. Examples ofcycloalkylidenyl radicals include, but are not limited to,cyclopentylidenyl, 3-fluorocyclohexylidenyl, and the like.

“Cycloalkyl-alkylidenyl” means a bivalent radical ═CRR′, wherein R is analkyl radical or hydrogen, and R′ is a cycloalkyl radical, as definedherein. Examples of cycloalkyl-alkylidenyl radicals include, but are notlimited to, cyclopropylmethylidenyl, cyclohexylmethylidenyl,1-cyclopentylethylidenyl, and the like.

“Cycloalkylalkyl-alkylidenyl” means a bivalent radical ═CRR′, wherein Ris an alkyl radical or hydrogen, and R′ is a cycloalkylalkyl radical, asdefined herein. Examples of cycloalkylalkyl-alkylidenyl radicalsinclude, but are not limited to, 2-cyclopentylethylidenyl,1-cyclohexylpropyliden-2-yl, and the like.

“Heteroalkylidenyl” means a bivalent radical ═CRR′, wherein R is anheteroalkyl radical, an haloalkyl radical, an alkyl radical, orhydrogen, and R′ is an heteroalkyl radical or an haloalkyl radical, asdefined herein. Examples of heteroalkylidenyl radicals include, but arenot limited to, 3,3,3-trifluoropropylidenyl, 2-hydroxybutylidenyl,3-aminopropylidenyl, and the like.

“Heterocyclylidenyl” means a bivalent radical ═CRR′, wherein R and R′are taken together with the carbon to which they are attached to form abivalent heterocyclyl radical, as defined herein. Examples ofheterocyclylidenyl radicals include, but are not limited to,pyrrolidinyliden-2-yl, tetrahydropyranyliden-4-yl, piperidinyliden-4-yl,and the like.

“Heterocyclyl-alkylidenyl” means a bivalent radical ═CRR′, wherein R isan alkyl radical or hydrogen, and R′ is an heterocyclyl radical, asdefined herein. Examples of heterocyclyl-alkylidenyl radicals include,but are not limited to, 4-piperidinylmethylidenyl,4-methyl-1-piperazinylmethylidene, and the like.

“Heterocyclylalkyl-alkylidenyl” means a bivalent radical ═CRR′, whereinR is an alkyl radical or hydrogen, and R′ is an heterocyclylalkylradical, as defined herein. Examples of heterocyclylalkyl-alkylidenylradicals include, but are not limited to,2-(tetrahydropyran-4-yl)ethylidenyl, 1-(piperidin-3-yl)propyliden-2-yl,and the like.

“Arylalkylidenyl” means a bivalent radical ═CRR′, wherein R is an arylradical, an alkyl radical, or hydrogen, and R′ is an aryl radical, asdefined herein. Examples of arylalkylidenyl radicals include, but arenot limited to, 4-chlorophenylmethylidenyl,6,7-dimethoxynaphth-2-ylmethylidenyl, and the like.

“Arylalkyl-alkylidenyl” means a bivalent radical ═CRR′, wherein R is analkyl radical or hydrogen, and R′ is an arylalkyl radical, as definedherein. Examples of arylalkyl-alkylidenyl radicals include, but are notlimited to, 2-(4-trifluoromethylphenyl)ethylidenyl,1-(3,4-dichlorophenyl)propyliden-2-yl, and the like.

“Heteroarylalkylidenyl” means a bivalent radical ═CRR′, wherein R is analkyl radical or hydrogen, and R′ is an heteroaryl radical, as definedherein. Examples of heteroarylalkylidenyl radicals include, but are notlimited to, 3-pyridinylmethylidenyl, 4-chloro-2-pyrimidinylmethylidenyl,and the like.

“Heteroarylalkyl-alkylidenyl” means a bivalent radical ═CRR′, wherein Ris an alkyl radical or hydrogen, and R′ is an heteroarylalkyl radical,as defined herein. Examples of heteroarylalkyl-alkylidenyl radicalsinclude, but are not limited to,2-(4-trifluoromethylpyrimidinyl)ethylidenyl,1-(thiophen-2-yl)propyliden-2-yl, and the like.

“Phenylsulfonyl” means a monovalent radical C₆H₅SO₂—. A phenyl group canbe unsubstituted or substituted with one or more suitable substituents.

“Alkoxycarbonyl” means a monovalent radical —C(O)—OR, wherein R is alower alkyl radical as defined herein. Examples of alkoxycarbonylradicals include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, butoxycarbonyl, and the like.

“Alkoxyalkylcarbonyl” means a monovalent radical —C(O)—R—OR′, wherein Ris an alkylene radical as defined herein and R′ is a lower alkyl radicalas defined herein. Examples of alkoxyalkylcarbonyl radicals include, butare not limited to, methoxymethylcarbonyl, ethoxymethylcarbohyl, and thelike.

It is contemplated that the definitions described herein may be appendedto form chemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like.

“Optional” or “optionally” means that a subsequently described event orcircumstance may but need not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optional bond” means that the bond may or maynot be present, and that the description includes single, double, ortriple bonds.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyinclude hydroxyl groups protected as acetates, haloalkyl carbonates,benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, and are preferablytert-butyl, benzyl or methyl esters.

“Amino-protecting group” means the protecting group that refers to thoseorganic groups intended to protect the nitrogen atom against undesirablereactions during synthetic procedures and includes, but is not limitedto, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It ispreferred to use either BOC or CBZ as the amino-protecting group becauseof the relative ease of removal, for example by exposure to mild acidsin the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid inethyl acetate as a solvent; or by catalytic hydrogenation in the case ofCBZ.

“Hydroxy-protecting group” means the protecting group that preserves ahydroxy group that otherwise would be modified by certain chemicalreactions. Suitable hydroxy-protecting groups include ether-forminggroups that can be removed easily after completion of all other reactionsteps, such as the benzyl or the trityl group optionally substituted intheir phenyl ring. Other suitable hydroxy-protecting groups includealkyl ether groups, the tetrahydropyranyl, silyl, trialkylsilyl ethergroups, and the allyl group.

“Deprotection” or “deprotecting” means the process by which a protectivegroup is removed after the selective reaction is completed. Certainprotective groups may be preferred over others due to their convenienceor relative ease of removal. Deprotecting reagents for protectedhydroxyl or carboxyl groups include potassium or sodium carbonates,lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid,trifluoroacetic acid, palladium catalysts, or boron tribromide, and thelike.

“Inert organic solvent” or “inert solvent” means the solvent inert underthe conditions of the reaction being described in conjunction therewith,including for example, benzene, toluene, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, chloroform, methylene chloride ordichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone,methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with one chiral center. It has twoenantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n-1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture.” When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London)1951, 612; Cahn et al. Experientia 1956,12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

“Atropic isomers” means the isomers owing their existence to restrictedrotation caused by hindrance of rotation of large groups about a centralbond.

“Substantially pure” means at least about 90 mole percent, morepreferably at least about 95 mole percent, and most preferably at leastabout 98 mole percent of the desired enantiomer or stereoisomer ispresent compared to other possible configurations.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

-   (1) acid addition salts formed with inorganic acids such as    hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,    phosphoric acid, and the like; or formed with organic acids such as    acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic    acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic    acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic    acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic    acid, malonic acid, mandelic acid, methanesulfonic acid, muconic    acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid,    succinic acid, tartaric acid, p-toluenesulfonic acid,    trimethylacetic acid, and the like; or-   (2) salts formed when an acidic proton present in the parent    compound either is replaced by a metal ion, e.g., an alkali metal    ion, an alkaline earth ion, or an aluminum ion; or coordinates with    an organic or inorganic base. Acceptable organic bases include    diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,    tromethamine, and the like. Acceptable inorganic bases include    aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium    carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium. It should be understood thatall references to pharmaceutically acceptable salts include solventaddition forms (solvates) or crystal forms (polymorphs) as definedherein, of the same acid addition salt.

“Crystal forms” (or polymorphs) means crystal structures in which acompound can crystallize in different crystal packing arrangements, allof which have the same elemental composition. Different crystal formsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Prodrug” or “pro-drug” means a pharmacologically inactive form of acompound which must be metabolized in vivo, e.g., by biological fluidsor enzymes, by a subject after administration into a pharmacologicallyactive form of the compound in order to produce the desiredpharmacological effect. Prodrugs of a compound of Formula I or FormulaII are prepared by modifying one or more functional group(s) present inthe compound of Formula I or Formula II in such a way that themodification(s) may be cleaved in vivo to release the parent compound.Prodrugs include compounds of Formula I or Formula II wherein a hydroxy,amino, sulfhydryl, carboxy or carbonyl group in a compound of Formula Ior Formula II is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonylgroup respectively. Examples of prodrugs include, but are not limitedto, esters (e.g. acetate, dialkylaminoacetates, formates, phosphates,sulfates and benzoate derivatives) and carbamates of hydroxy functionalgroups (e.g. N,N-dimethylcarbonyl), .esters of carboxyl functionalgroups (e.g. ethyl esters, morpholinoethanol esters), N-acyl derivatives(e.g. N-acetyl), N-Mannich bases, Schiff bases and enaminones of aminofunctional groups, oximes, acetals, ketals, and enol esters of ketonesand aldehyde functional groups in compounds of Formula I or Formula II,and the like.

The prodrug can be metabolized before absorption, during absorption,after absorption, or at a specific site. Although metabolism occurs formany compounds primarily in the liver, almost all other tissues andorgans, especially the lung, are able to carry out varying degrees ofmetabolism. Prodrug forms of compounds may be utilized, for example, toimprove bioavailability, improve subject acceptability such as bymasking or reducing unpleasant characteristics such as bitter taste orgastrointestinal irritability, alter solubility such as for intravenoususe, provide for prolonged or sustained release or delivery, improveease of formulation, or provide site-specific delivery of the compound.Reference to a compound herein includes prodrug forms of a compound.Prodrugs are described in The Organic Chemistry of Drug Design and DrugAction, by Richard B. Silverman, Academic Press, San Diego, 1992.Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352–401; Design ofProdrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

“Subject” means mammals and non-mammals. Mammals means any member of theMammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

“Disease state” means any disease, condition, symptom, or indication.

“Treating” or “treatment” of a disease state includes:

-   (1) preventing the disease state, i.e. causing the clinical symptoms    of the disease state not to develop in a subject that may be exposed    to or predisposed to the disease state, but does not yet experience    or display symptoms of the disease state;-   (2) inhibiting the disease state, i.e., arresting the development of    the disease state or its clinical symptoms, or-   (3) relieving the disease state, i.e., causing temporary or    permanent regression of the disease state or its clinical symptoms.

“Mood disorders” or “affective disorders” means psychopathologicconditions in which a pervasive disturbance of mood constitutes the coremanifestation. These terms subsume anxiety and related neuroses,especially the depressive form. Examples of “mood disorders” or“affective disorders” include, but are not limited to, depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,unipolar disorder, bipolar disorder with manifestations of insomnia andeating disorder, dysthymic disorder, double depression, morbid andclinical depression, mania and cyclothymia.

Nomenclature

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

For example, a compound of Formula I wherein R¹ is 4-hydroxyheptan-4-yl,R² is methyl, R³, and R⁴ are hydrogen, Ar is2-chloro-4,6-dimethyl-phenyl, and n is 1 is named4-[7-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-heptan-4-ol.

General Utility

The compounds of this invention are CRF antagonists, and as such areexpected to be effective in the treatment of a wide range ofstress-related illnesses, mood disorders such as depression, majordepressive disorder, single episode depression, recurrent depression,child abuse induced depression, postpartum depression, dysthemia,bipolar disorder and cyclothymia; chronic fatigue syndrome; eatingdisorders such as obesity, anorexia and bulimia nervosa; generalizedanxiety disorder; panic disorder; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; pain perception such asfibromyalgia; headache; stress-induced gastrointestinal dysfunction suchas irritable bowel syndrome (IBS), colonic hypersensitivity or spasticcolon; hemorrhagic stress; ulcers; stress-induced psychotic episodes;inflammatory disorders such as rheumatoid arthritis and osteoarthritis;asthma; psoriasis; allergies; premature birth; hypertension; congestiveheart failure; sleep disorders; neurodegenerative diseases such asAlzheimer's disease, senile dementia, Parkinsons's disease andHuntington's disease; head or spinal cord trauma; ischemic neuronaldamage; excitotoxic neuronal damage; epilepsy; stroke; psychosocialdwarfism; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms; stress-induced immune dysfunctions; immunesuppression and stress-induced infections; cardiovascular or heartrelated diseases; fertility problems; and/or human immunodeficiencyvirus infections.

These and other therapeutic uses are described, for example, in Goodman& Gilman's, The Pharmacological Basis of Therapeutics, ninth edition,McGraw-Hill, New York, 1996, Chapter 26:601–616; and Coleman, R. A.,Pharmacological Reviews, 1994, 46:205–229.

Testing

The pharmacology of the compounds of this invention was determined byart recognized procedures. The CRF receptor binding affinity of testcompounds can be determined by the intracellular CRF stimulated cAMPactivity assay and the CRF Receptor Binding Assay as described in moredetail in Example 3 and 4 respectively.

Compound Preparation

The compounds of Formulae I and II described herein may be prepared bystandard synthetic methods. In particular, certain compounds of FormulaeI and II may be prepared from intermediate bromopyrazole 7, thepreparation of which is illustrated in Scheme 1 for Formula I, where R²,R³, R⁴, and n are as described above, and Ar, as described above, is forexample phenyl optionally-substituted with one or more groups X.

According to Scheme 1, optionally substituted aniline 1 is acylated witha carboxylic acid derivative, optionally substituted with groups R³ andR⁴, having an ω-leaving group, such as halogen, to provide amide 2,which is subsequently cyclized under basic conditions onto the carbonpossessing the leaving group to generate 3. Anilide lactam 3 isconverted into the corresponding thione 4, deprotonated, C-acylated, andconcurrently S-methylated to form methyl carboxylate 5. Treatment of 5with R²-substituted hydrazine provides pyrazolinone-fused heterocycle 6,which is brominated to provide bromopyrazole 7. The pyrazole-fusedheterocycles can also be similarly prepared with an aminoheteroaryl inplace of the aniline. For example, compound 12d (Table 7) is preparedstarting from 2-dimethylamino-4-methyl-5-amino pyridine (T. Ebara et al.JP54028330 [CAN 91:40904])

Intermediate bromopyrazole 7 is converted into the compounds of FormulaeI and II, as illustrated in Scheme 2 for Formula I, where R², R³, R⁴,R^(d), R^(e), and n are as described above, and Ar, as described above,is for example phenyl optionally-substituted with one or more groups X.

According to Scheme 2, intermediate bromopyrazole 7 is metallated andreacted with an R^(d),R⁵-substituted aldehyde or ketone to providealcohol 8a which may be eliminated to the corresponding alkene 9. It isappreciated that depending upon the reaction conditions, and the natureof R^(d) and R⁵, the double bond stereochemistry resulting from theelimination reaction to alkene.9 may be either an E-double bond, aZ-double bond, or a mixture of both in various ratios. Subsequentreduction of alkene 9, by hydrogenation for example, provides alkane 10.It is understood that R^(e) as defined above corresponds to CH₂—R⁵ orCH—R⁵ of alcohol 8a or alkene 9, respectively. Alternatively,bromopyrazole 7 is metallated and reacted with anR^(d),R^(e)-substituted aldehyde or ketone to provide alcohol 8b whichmay be deoxygenated, under radical conditions for example, to providealkane 10.

Alternatively, intermediate bromopyrazole 7 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 3 for FormulaI, where R², R³, R⁴, R^(a), R^(b), and n are as described above, and Ar,as described above, is for example phenyl optionally-substituted withone or more groups X.

According to Scheme 3, intermediate bromopyrazole 7 is metallated andreacted with carbon dioxide, or a carbon dioxide equivalent, to providecarboxylic acid 11. Acid 11 is converted to the corresponding amine 13via an amide rearrangement, such as by the Curtius, Lossen, or Schmidtreaction, or as illustrated in Scheme 3 by the Hofmann reactioninvolving intermediate carbamate 12. Amine 13 is converted into themono- or disubstituted amine 14 by reductive amination or successivereductive amination, respectively, using an appropriate aldehyde orketone, and a reducing agent, such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like. Alternatively, amine 13 isconverted into mono- or disubstituted amine 14 via acylation with anappropriate carboxlic acid derivative, such as the corresponding acidchloride, and reduction with an appropriate reducing agent such asdiborane, borane-THF complex, and the like. Another alternativeconversion of amine 13 to mono- or disubstituted amine 14 is viaalkylation with an appropriate alkylating agent, such as methyl iodide,ethyl bromide, and the like, optionally under basic conditions. It isappreciated that each substituent R^(a) and R^(b) may be introducedusing the same synthetic route described herein, or each substituent maybe introduced by a different synthetic route described herein.

Alternatively, intermediate carboxylic acid 11 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 4 for FormulaI, where R², R³, R⁴, R^(a), R^(b), and n are as described above, and Ar,as described above, is for example phenyl optionally-substituted withone or more groups X.

According to Scheme 4, intermediate acid 11 is converted into thecorresponding amide 15 and may be further reduced to amine 16.

Alternatively, pyrazolinone-fused heterocyclic 6 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 5 for Formulal, where R², R³, R⁴, R^(a), and n are as described above, and Ar, asdescribed above, is for example phenyl optionally-substituted with oneor more groups X.

According to Scheme 5, intermediate pyrazolinone-fused heterocycle 6 isconverted into the corresponding alkoxypyrazole-fused heterocycle 17.

Alternatively, intermediate bromopyrazole 7 is converted into thecompounds of Formulae I and II, as illustrated in Scheme 6 for FormulaI, where R², R³, R⁴, and n are as described above, and Ar, as describedabove, is for example phenyl optionally-substituted with one or moregroups X.

According to Scheme 6, intermediate bromopyrazole 7 is subjected to ametal-catalyzed aryl coupling reaction to provide an aryl pyrazole, asillustrated by, for example phenyl pyrazole 18, optionally substitutedwith one or more groups Y.

It is understood that the synthetic routes illustrated in Schemes 1–6are suitable for preparing other compounds of Formulae I and II,including those compounds where Ar, as defined above, is for examplenaphthyl, pyrimidinyl, or pyridinyl, each of which may be optionallysubstituted. It is also appreciated that R² as pertains to theillustrative synthetic sequences of Schemes 1–6 may be a protectinggroup, as defined above, which may be conveniently removed to provide R²as hydrogen, or to introduce R² as alkyl, aryl, acyl, or alkylsulfonyl,as defined above.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1–500 mg daily, preferably 1–100 mg daily, and mostpreferably 1–30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agelin the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subderrhal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Example 2.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures), but allowance for some experimental errorand deviation, including differences in calibration, rounding ofnumbers, and the like, is contemplated.

Example 13-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

Step 1 5-Chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide

To a solution of 2-chloro-4,6-dimethylaniline (14.7 g) anddiisopropylethylamine (18 mL) in 150 mL of THF, was added a solution of5-chlorovaleryl chloride (12.2 mL) in 75 mL of THF. After the reactionmixture had been allowed to stir at room temperature overnight, it wasfiltered and the filtrate concentrated on the rotary evaporator. Theresidue was dissolved in ethyl acetate and washed with 1 M aqueous HCl,saturated aqueous sodium bicarbonate, and brine. The ethyl acetatesolution was then dried with magnesium sulfate and concentrated on therotary evaporator to give a solid which was combined with a 1:1 mixtureof hexane and diethyl ether. After this mixture had been stirred for anhour, it was filtered and the collected solids were dried to provide12.2 g of 5-chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide, mp80.6–82.9° C.

Step 2 1-(2-Chloro-4,6-dimethylphenyl)piperidin-2-one

5-Chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide (21.7 g),potassium t-butoxide (9.34 g), and sodium iodide (1.2 g) were combinedin 200 mL t-butanol and the mixture was stirred in a 60° C. oil bath for3 h. After cooling to room temperature, the reaction mixture waspartitioned between ethyl acetate and water. The aqueous phase waswashed with additional ethyl acetate. The organic phases were washedwith brine, dried with magnesium sulfate, and concentrated to give 18.9g of 1-(2-chloro-4,6-dimethylphenyl)piperidin-2-one as a solid, mp.107.7–108.7° C.

Step 3 1-(2-Chloro-4,6-dimethylphenyl)piperidine-2-thione

1-(2-Chloro-4,6-dimethylphenyl)piperidin-2-one (18.8 g) and Lawesson'sreagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](19.2 g) were combined in 150 mL toluene and the mixture was stirred inan 80° C. oil bath for 3 h. The reaction mixture was then cooled to roomtemperature and filtered. The filtrate was concentrated on the rotaryevaporator and the residue was chromatographed on silica gel, elutingwith 9:1 hexane/acetone, to provide 19.4 g of1-(2-chloro-4,6-dimethylphenyl)piperidine-2-thione, mp 146.8–148.0° C.

Step 41-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicAcid Methyl Ester

1-(2-Chloro-4,6-dimethylphenyl)piperidine-2-thione (5.11 g), dimethylcarbonate (17.0 mL), sodium hydride (3.7 g of a 60% dispersion inmineral oil), and methanol (0.5 mL) were combined in 100 mL of dioxaneand the mixture was stirred in a 120° C. oil bath for 4 h. After thereaction had cooled to room temperature, it was quenched by the additionof aqueous ammonium chloride, diluted with water and washed twice withethyl acetate. After drying over magnesium sulfate, the ethyl acetatewas concentrated and the residue chromatographed on silica gel using anacetone/hexane gradient to provide 5.00 g1-(2-chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester, mp 85.3–87.6° C.

Step 57-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one

1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester (4.99 g), methylhydrazine (16.4 mL), p-toluenesulfonicacid monohydrate (2.91 g), and methanol (75 mL) were combined in a glassvessel sealed with a Telfon™ screw cap. The reaction mixture was stirredin a 130° C. oil bath for 24 h, then cooled to room temperature andconcentrated on the rotary evaporator. The residue was chromatographedon silica gel using a methanol/dichloromethane gradient to give 3.21 gof7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one,mp 95.9–99.9° C.

Step 63-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one(3.16 g) and phosphorus oxybromide (15.5 g) were combined and stirred ina 110° C. oil bath for 4 h. After the reaction mixture had cooled toroom temperature, it was dissolved in dichloromethane and added to 200mL of ice/water. This mixture was stirred vigorously for 30 min. Thephases were then separated and the aqueous phase was washed withadditional dichloromethane. The combined organic phases were washed withaqueous sodium bicarbonate, dried with magnesium sulfate, andconcentrated on the rotary evaporator. The residue was chromatographedon silica gel eluting with an acetone/hexane gradient to provide 1.16 gof3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,mp 106–107° C.

Example 23-Bromo-7-(2,4-dichlorophenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

Example 2 was prepared according the procedure described in Example 1,except that 2-chloro-4,6-dimethylaniline was replaced by2,4-dichloroaniline in step 1, and step 4 was performed as follows:

1-(2,4-Dichlorophenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicAcid Methyl Ester

To 39.6 ml of a 3M solution ethylmagnesium bromide in ether was added100 mL of dry tetrahydrofuran under an atmosphere of nitrogen. Then 16.7mL of diisopropylamine was added dropwise. The reaction mixture was thenheated to 80° C. for 1 h. After cooling to room temperature, the mixturewas treated with a solution of 6.19 g of1-(2,4-dichlorophenyl)piperidine-2-thione in 50 mL of drytetrahydrofuran, heated to 80° C. for 30 min, and cooled again to roomtemperature. Then the mixture was treated dropwise with 10.0 mL ofdimethylcarbonate and heated to 80° C. for 26 h. After cooling to roomtemperature, 100 g of ice was added along with 150 mL of 1.2M HCl. Themixture was extracted three times with 100 mL portions ofdichloromethane. The combined organic extracts were washed with 100 mLof brine, dried over magnesium sulfate, concentrated, and then keptunder high vacuum at 50° C. to remove the higher boiling volatilematerials. The residue was purified by flash silica gel chromatographyusing 7% acetone/hexane as solvent yielding 5.25 g of1-(2,4-dichlorophenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylicacid methyl ester as a yellow solid, mp 83–86° C.

Examples 3–4

Example 3 was prepared according to the procedure described in Example1, except that 2-chloro-4,6-dimethylaniline was replaced by2,4,6-trimethylaniline in step 1.

Example 4 was prepared according the procedure described in Example 1,except that 2-chloro-4,6-dimethylaniline was replaced by2,4,6-trimethylaniline, and 5-chlorovaleryl chloride was replaced by6-chlorocaproyl chloride in step 1.

TABLE 1 Compounds prepared in Examples 1–4. MH+ mp observed ExampleStructure Name (° C.) (predicted) 1

3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine106–107 354 (354) 2

3-Bromo-7-(2,4-dichloro-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine360 (360) 3

3-Bromo-2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine94.6–97.9 334 (334) 4

3-Bromo-2-methyl-8-(2,4,6-trimethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triaza-azulene348 (348)

Example 5a4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-gyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol

3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(122 mg) and a crystal of 1,10-phenanthroline were dissolved in 3 mL ofdry tetrahydrofuran and the solution was chilled to −78° C. under anatmosphere of argon. Then nbutyllithium (2.0 M in cyclohexane) was addeduntil the dark color of the organolithium/phenanthroline complexpersisted. An additional 0.17 mL of the butyllithium solution then wasadded. After 10 min, a solution of 4-heptanone (42.6 mg) in 1 mLtetrahydrofuran was added via syringe. The reaction mixture was allowedto stir at −78° C. for 15 min, then was allowed to warm to 0° C. Afterquenching with aqueous ammonium chloride, the reaction mixture waspartitioned between ethyl acetate and brine. The ethyl acetate was driedwith magnesium sulfate and concentrated on the rotary evaporator. Theresidue was chromatographed on silica gel eluting with 9:1hexane/acetone to provide 76.0 mg of4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol,which was recrystallized from hexane, mp 129–130 ° C.

Examples 5b–5m

Example 5b was prepared according to the procedure described in Example5a, except that the compound from Example 1 was replaced with thecompound from Example 3.

Example 5c was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with 1-thienylbutanone and thecompound from Example 1 was replaced with the compound from Example 3.

Example 5d was prepared according to the procedure described in Example5a, except that the compound from Example 1 was replaced with thecompound from Example 4.

Example 5e was prepared according to the procedure described in Example5a, except that the compound from Example 1 was replaced with thecompound from Example 2.

Example 5f was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with 1,3-bismethoxypropan-2-oneand the compound from Example 1 was replaced with the compound fromExample 3.

Example 5g was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with 1,4-bismethoxybutan-2-oneand the compound from Example 1 was replaced with the compound fromExample 3.

Example 5h was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with 1-thiazol-2-ylpropanoneand the compound from Example 1 was replaced with the compound fromExample 3.

Example 5i was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with 2-furancarboxaldehyde andthe compound from Example 1 was replaced with the compound from Example3.

Example 5j was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with propanal and the compoundfrom Example 1 was replaced with the compound from Example 3.

Example 5k was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with1-(1-ethylimidazol-2-yl)butanone and the compound from Example 1 wasreplaced with the compound from Example 3.

Example 5l was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with tetrahydropyran-4-one andthe compound from Example 1 was replaced with the compound from Example3.

Example 5m was prepared according to the procedure described in Example5a, except that 4-heptanone was replaced with water.

TABLE 2 Compounds prepared in Examples 5. MH+ mp observed ExampleStructure Name (° C.) (predicted) 5a

4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol129–130 390 (390) 5b

4-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol  126–127.9 370 (370) 5c

1-[82-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-1-thiophen-2-ylbutan-1-ol175.9–178.4 410 (410) 5d

4-[2-Methyl-8-(2,4,6-trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulen-3-yl]heptan-4-ol  87–91.1 384 (384) 5e

4-[7-(2,4-Dichlorophenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol121.4–122.6 396 (396) 5f

1,3-Dimethoxy-2-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propan-2-ol120.3–121.8 374 (374) 5g

1,4-Dimethoxy-2-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]butan-2-ol107.9–110.9 388 (388) 5h

1-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-1-thiazol-2-ylbutan-1-ol160.1–165.6 411 (411) 5i

Furan-2-yl[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanol163.1–174.4 352 (352) 5j

1-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propan-1-ol179.4–180.9 314 (314) 5k

1-(1-Ethyl-1H-imidazol-2-yl)-1-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]butan-1ol 94.9–100.9 422 (422) 5l

4-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]tetrahydropyran-4-ol  193–195.1 356 (356) 5m

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine97–98 276 (276)

Example 6a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol(594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in13 mL toluene and the stirred mixture was heated to 110° C. for 11 h.The reaction mixture was then cooled to room temperature and partitionedbetween ethyl acetate and aqueous sodium bicarbonate. The aqueous phasewas washed with additional ethyl acetate. The combined ethyl acetate waswashed with brine, dried with magnesium sulfate, and concentrated. Theresidue was chromatographed on silica gel eluting with an acetone/hexanegradient to provide 461 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,which was recrystallized from hexane, mp 86.7–88.2° C.

Examples 6b–6f

Example 6b was prepared according to the procedure described in Example6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5b.

Example 6c was prepared according to the procedure described in Example6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5c.

Example 6d was prepared according to the procedure described in Example6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5d.

Example 6e was prepared according to the procedure described in Example6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5e.

Example 6f was prepared according to the procedure described in Example6a, except that4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-olwas replaced by the compound from Example 5h.

TABLE 3 Compounds prepared in Examples 6. MH+ mp observed ExampleStructure Name (° C.) (predicted) 6a

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine86.7–88.2 372 (372) 6b

2-Methyl-3-(1-propylbut-1-enyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine101.6–102.6 352 (352) 6c

2-Methyl-3-(1-thiophen-2-ylbut-1-enyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineoil 392 (392) 6d

2-Methyl-3-(1-propylbut-1-enyl)-8-(2,4,6-trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulene101.9–103.9 366 (366) 6e

7-(2,4-Dichlorophenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineoil 378 (378) 6f

2-Methyl-3-(1-thiazol-2-ylbut-1-enyl)-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine393 (393)

Example 7a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(41.5 mg) was dissolved in acetic acid (1 mL) and 12 mg of 10% palladiumon carbon was added. The mixture was stirred under hydrogen at oneatmosphere for 12 h. The mixture was diluted with ethyl acetate andfiltered through diatomaceous earth which was then washed with ethylacetate. The ethyl acetate filtrate was washed with aqueous sodiumbicarbonate, dried with magnesium sulfate, and concentrated. The residuewas chromatographed on silica gel eluting with an acetone/hexanegradient to provide 10.2 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,as a crystalline film, ms m/z 374 (MH⁺).

Examples 7b–7d

Example 7b was prepared according to the procedure described in Example7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2Hpyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6b.

Example 7c was prepared according to the procedure described in Example7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6c.

Example 7d was prepared according to the procedure described in Example7a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 6d.

TABLE 4 Compounds prepared in Examples 7. MH+ mp observed ExampleStructure Name (° C.) (predicted) 7a

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine374 (374) 7b

2-Methyl-3-(1-propylbutyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine91.5–92   354 (354) 7c

2-Methyl-3-(1-thiophen-2-ylbutyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine87.6–90.3 394 (394) 7d

2-Methyl-3-(1-propylbutyl)-8-(2,4,6-trimethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,8-triazaazulene96.0–98.1 368 (368)

Example 8a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicAcid

3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine(1.46 g) and a few crystals of 1, 10 phenanthroline were dissolved in 25mL of dry tetrahydrofuran and chilled to −78° C. under an atmosphere ofargon. Then a 2.0 M solution of n-butyllithium in cyclohexane was addeddropwise until the dark color of the phenanthroline/organolithiumcomplex persisted. Then an additional 2.05 mL of the n-butyllithiumsolution was added. After 10 minutes, carbon dioxide, generated from dryice, was bubbled through the reaction mixture for 5 minutes. After thereaction mixture had been stirred at −78° C. for 5 minutes, the coolingbath was removed and the mixture was allowed to warm for 5 minutesbefore being quenched by the addition of water. The mixture was combinedwith ethyl acetate and water, acidified with dilute hydrochloric acid,and the phases separated. The ethyl acetate was dried with magnesiumsulfate and concentrated. The residue was chromatographed on silica geleluting with an acetone/hexane gradient to provide 1.11 g of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid, mp 247.8–248.3° C.

Example 8b7-(2,4,6-Trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicAcid

Example 8b was prepared according to the procedure described in Example8a, except that3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinewas replaced by the compound from Example 3.

Example 8c[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicAcid Tert-butyl Ester

A 159 mg sample of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid was combined with 2.5 mL of t-butanol and 140 μL of triethylaminewas added. Then 129 μL of diphenylphosphoryl azide was added and thereaction mixture was heated to 85° C. for 2 h. After cooling to roomtemperature, the reaction mixture was dissolved in ethyl acetate andwashed with 1M aqueous sodium bisulfate, aqueous sodium bicarbonate,water, and brine. The ethyl acetate solution was dried with magnesiumsulfate and concentrated to give material which was chromatographed onsilica gel eluting with an acetone/hexane gradient. Product containingfractions were concentrated to give a solid residue which was slurriedin a small amount of boiling hexane. After the mixture cooled to roomtemperature, the solids were collected by filtration to provide 71 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid tert-butyl ester, mp 171.4–175.7° C.

Example 8d

Example 8d was prepared according to the procedure described in Example8c, except that t-butanol was replaced by ethanol.

Example 9a[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine

Step 17-(2-Chloro-4,6-dimethylihenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine

To a 0° C. solution of 287 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid tert-butyl ester (Example 8c) in 9 mL of dichloromethane, was added3 mL of trifluoroacetic acid. After 15 min, the cooling bath was removedand the reaction mixture was allowed to stir and warm to roomtemperature during 3 h. The reaction mixture was then diluted withdichloromethane and washed with dilute aqueous sodium hydroxide. Theaqueous phase was washed with additional dichloromethane, after whichthe combined organics were dried with magnesium sulfate andconcentrated. The residue was chromatographed on silica gel eluting witha methanol/dichloromethane gradient to provide 182 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine,mp 234–236° C.

Step 2[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine

To a solution of 55 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylaminein 3 mL of dichloroethane was added 29 μL of propionaldehyde followed afew minutes later by 124 mg of sodium triacetoxyborohydride. Thereaction mixture was stirred at room temperature for 2 d, during whichtime an additional 30 μL of propionaldehyde and an additional 62 mg ofsodium triacetoxyborohydride were added to drive the reaction tocompletion. The mixture was then diluted with dichloromethane and washedwith dilute aqueous sodium hydroxide. The organics were dried overmagnesium sulfate and concentrated. The residue was chromatographed onsilica gel eluting with an acetone/hexane gradient to provide a solidwhich was recrystallized from hexane to give 17 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine,mp 90–91° C.

Example 9b

Example 9b was prepared according to the procedure described in Example9a, except that step 2 was performed as follows:

Step 2[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amine

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(45.7 mg) and 4-heptanone (24 μL) were dissolved and stirred in 3 mL ofdichloroethane. After 15 min, 44.5 mg of sodium triacetoxyborohydridewas added. The reaction mixture was stirred at 60° C. during the day andat room temperature over night during 3 d. During this period, anadditional 109 μL of 4-heptanone and an additional 104 mg of sodiumtriacetoxyborohydride were added to drive the reaction to completion.The reaction mixture was then partitioned between ethyl acetate andwater. The ethyl acetate was dried with magnesium sulfate andconcentrated. The crude product was chromatographed on silica geleluting with an acetone/hexane gradient to provide 11 mg of[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amineas a crystalline film, ms m/z 389 (MH⁺).

Example 9c[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine

Step 1N-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide

To a stirred solution of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(0.51 g) and triethylamine (0.27 mL) in dichloromethane (40 mL) at 0° C.was added propionyl chloride (0.17 mL) in dichloromethane (10 mL)dropwise over 25 minutes. The resulting mixture was stirred for anadditional 1 hour at 0° C., followed by 14 hours at room temperature.The reaction mixture was then stirred with an aqueous 5% citric acidsolution (40 mL) for 10 minutes. The layers were separated, and theaqueous layer was further extracted with dichloromethane (50 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate, thendecanted from the desiccating agent and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography using a dichloromethane/methanol gradient to affordN-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide(0.49 g) as an off white solid, ms m/z 347 (MH⁺).

Step 2[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine

To a stirred, chilled (0° C.) solution ofN-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide(0.48 g) in tetrahydrofuran (9 mL), under nitrogen, was added borane-THFcomplex (4.1 mL of a 1.0 M tetrahydrofuran solution) in one portion. Theresulting mixture was stirred for 1 hour at 0° C., then stirred for 48hours at room temperature. The reaction mixture was then treated with1:2 acetic acid/ethyl acetate (11 mL), mixed briefly, and allowed tostand at room temperature for 24 hours. The resulting mixture was addedto a 3% aqueous sodium hydroxide solution (75 mL), and extracted withethyl acetate (3×75 mL). The combined organic extracts were dried overanhydrous sodium sulfate, then decanted from the desiccating agent andconcentrated under reduced pressure to provide, without furtherpurification,[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine(0.45 g), as a pale yellow solid, ms m/z 333 (MH⁺).

Step 3[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine

[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine(17 mg) was treated with a solution of 2-furancarboxaldehyde (9 mg) in1,2-dichloroethane (0.38 mL). To the resulting mixture was then addedacetic acid (15 mg), followed by sodium triacetoxyborohydride (30 mg).At room temperature, the resulting mixture was agitated for 72 hoursusing a rotary shaker. The reaction mixture was then treated withsaturated aqueous sodium bicarbonate (2 mL) and extracted with ethylacetate (3×2 mL). The combined organic extracts were then concentratedunder reduced pressure. The resulting orange-yellow residue was purifiedby preparative high-pressure liquid chromatography (HPLC) onreversed-phase (C18) silica gel (gradient, acetonitrile-0.1%trifluoroacetic acid=10:90 to 90:10) to afford[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]furan-2-ylmethylpropylamine,trifluoroacetate salt (5 mg) as a yellow solid, ms m/z 413 (MH⁺).

Examples 9d–9ai

Example 9d was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced bypyridine-2-carboxaldehyde in step 3.

Example 9e was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced bypyridine-4-carboxaldehyde in step 3.

Example 9f was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced byimidazole-2-carboxaldehyde in step 3.

Example 9g was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced bypyridine-3-carboxaldehyde in step 3.

Example 9h was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced byimidazole-4-carboxaldehyde in step 3.

Example 9i was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced by3,4,5-trimethoxybenzaldehyde in step 3.

Example 9j was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced by2,3,4-trimethoxybenzaldehyde in step 3.

Example 9k was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced by1-methylimidazole-4-carboxaldehyde in step 3.

Example 9l was prepared according to the procedure described in Example9c, except that 2-furancarboxaldehyde was replaced by3-methylimidazole-4-carboxaldehyde in step 3.

Examples 9m–9ae and 9ai in Table 5 were prepared by reductive aminationas described in step 3 of Example 9c with the appropriate secondaryamines and aldehyde. The secondary amines were prepared by reduction ofamides 10c and 10d (Table 6) as described in step 2 of Example 9c.

Example 9af(1-Methoxymethylpropyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine

2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(101 mg, 0.373 mmol) was dissolved in CH₂Cl₂ (2 mL). Et₃N (0.25 mL, 1.79mmol) and the 1-methoxy-butan-2-one (65 mg, 0.636 mmol) were added atroom temperature. A solution of TiCl₄ in toluene (1 M; 0.35 mL, 0.35mmol) was added dropwise via syringe. The mixture was then stirred atroom temperature overnight. NaCNBH₃ (120 mg, 1.9 mmol) in methanol (1mL) was added slowly. The stirring continued at room temperature for 0.5h and the reaction was quenched by the addition of 2 N NaOH (2 mL).EtOAc was added and the layers were separated. The organic layer waswashed with water, brine and dried over MgSO₄ The solvent was removedand the residue purified by chromatography on SiO₂, (gradient elution:2% MeOH in CH₂Cl₂ containing 0.1% NH₄OH to 3% MeOH in CH₂Cl₂ containing0.15% NH₄OH over 20 minutes) to yield 102 mg of product (0.286 mmol;77%).

Examples 9ag, 9ah, 9aj and 9ak were prepared in analogous fashion using3-pentanone, 1,3-dimethoxypropan-2-one, and 1,4-dimethoxypentan-2-one.

Example 9al was prepared using the appropriate methodology describedhereinabove to prepare propyl7-(2,4,6-trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylaminewhich is reacted with phenylsulfonyl chloride utilizing Schotten-Baumanconditions.

TABLE 5 Compounds prepared in Examples 8–9. MH+ mp observed ExampleStructure Name (° C.) (predicted) 8a

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid 247.8–248.3 320 (320) 8b

7-(2,4,6-Trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid 228.6–233.9 300 (300) 8c

[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid tert-butyl ester 171.4–175.7 391 (391) 8d

[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamicacid ethyl ester 204.0–207.8 363 (363) 9a

[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]dipropylamine90–91 375 (375) 9b

[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amine389 (389) 9c

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-furan-2-ylmethyl-propyl-aminetrifluoroaceticacid salt 413 (413) 9d

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-pyridin-2-ylmethyl-aminetrifluoroaceticacid salt 424 (424) 9e

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-pyridin-4-ylmethyl-aminetrifluoroaceticacid salt 424 (424) 9f

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(1H-imidazol-2-ylmethyl)-propyl-aminetrifluoroaceticacid salt 413 (413) 9g

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-pyridin-3-ylmethyl-aminetrifluoroaceticacid salt 424 (424) 9h

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(1H-imidazol-4-ylmethyl)-propyl-aminetrifluoroaceticacid salt 413 (413) 9i

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-(3,4,5-trimethoxy-benzyl)-aminetrifluoroaceticacid salt 513 (513) 9j

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propyl-(2,3,4-trimethoxy-benzyl)-aminetrifluoroaceticacid salt 513 (513) 9k

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl-(1-methyl-1H-imidazol-4-ylmethyl)-propyl-aminetrifluoroacetic acidsalt 427 (427) 9l

[7-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(3-methyl-3H-imidazol-4-ylmethyl)-propyl-aminetrifluoroacetic acidsalt 427 (427) 9m

(2-Methoxy-ethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]thiazol-2-ylmethylamine,trifluoroacetic acid salt 426 (426) 9n

Furan-2-ylmethyl-(2-methoxy-ethyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]amine,trifluoroacetic acid salt 409 (409) 9o

(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-(3,4,5-trimethoxy-benzyl)amine,trifluoroaceticacid salt 509 (509) 9p

4({(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]amino}methyl)benzonitrile,trifluoroaceticacid salt 444 (444) 9q

(2-Methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propylamine,trifluoroaceticacid salt 371 (371) 9r

(3,4-Dimethoxybenzyl)-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine,trifluoroaceticacid salt 479 (479) 9s

Cyclopropylmethyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amineoil 383 (383) 9t

Benzyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine,trifluoroacetic acid salt 419 (419) 9u

Butyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine,trifluoroacetic acid salt 385 (385) 9v

[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylthiazol-2-ylmethylamine,trifluoroacetic acid salt 410 (410) 9w

4-({[2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamino}-methyl)-benzonitrile,trifluoroacetic acid salt 428 (428) 9x

(3,4-Dimethoxybenzyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamine,trifluoroaceticacid salt 463 (463) 9y

Cyclopropylmethyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamine,trifluoroaceticacid salt 367 (367) 9z

Benzyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazoIo[3,4-b]pyridin-3-yl]-proprylamine,trifluoroaceticacid salt 403 (403) 9aa

Butyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamine,trifluoroaceticacid salt 369 (369) 9ab

[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylthiophen-2-ylmethylamine,trifluoroacetic acid salt 409 (409) 9ac

Ethyl-(2-methoxyethyl)-[2-methyl-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amineoil 357 (357) 9ad

Ethyl-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-propylamineoil 341 (341) 9ae

[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-dipropylamine88.9–91.5 355 (355) 9af

(1-Ethylpropyl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine 99.3–104.9 341 (341) 9ag

(2-Methoxy-1-methoxymethylethyl)-[2-methyl-7-(2,4,6-trimethyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amineoil 373 (373) 9ah

(3-Methoxy-1-methoxymethylpropyl)-[2-methyl-7-(2,4,6-trimethyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amineoil 387 (387) 9ai

Cyclopropylmethyl-(2-methoxyethyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amineoil 383 (383) 9aj

(1-Methoxymethylpropyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine 96.5–102.5 357 (357) 9ak

(1-Methoxymethylbutyl)-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-amine100.1–104.4 371 (371) 9al

N-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-N-propylbenzenesulfonamide,trifluoroaceticacid salt 453 (453)

Example 10a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicAcid Cyclopropylmethylpropylamide

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid (107.0 mg), 1-hydroxybenzotriazole hydrate (50.3 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.5 mg),triethylamine (93 μL), and N-propylcyclopropanemethylamine (49 μL) werecombined in 4 mL of dichloromethane and stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetateand 1M hydrochloric acid. The ethyl acetate solution was washed withaqueous sodium bicarbonate, dried with magnesium sulfate, andconcentrated. The crude product was chromatographed on silica geleluting with an acetone/hexane gradient giving a solid.Recrystallization from hexane provided 75.6 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid cyclopropylmethylpropylamide, mp 120.6–122.0° C.

Example 10b(3,4-Dihydro-1H-isoquinolyl-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanone

A suspension of 125 mg of2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacid in 5 mL of dichloromethane was treated with 116 μL oftriethylamine, 56 mg of 1-hydroxybenzotriazole hydrate, 88 mg of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 52 μLof 1,2,3,4-tetrahydroisoquinoline and stirred under an atmosphere ofnitrogen at room temperature for 20 h. The mixture was diluted with 50mL of ethyl acetate, washed with 30 mL of 0.5M HCl, washed with 30 mL ofsaturated sodium bicarbonate solution, dried over magnesium sulfate, andevaporated to dryness yielding 149 mg of(3,4-dihydro-1H-isoquinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanone,mp 80.3–87.7° C.

Example 10c was prepared by acylation of2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(prepared from example 8b using procedures described for examples 8c and9a; step 1) with propionyl chloride.

Example 10d was prepared by acylation of7-(2,4,6-trimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine(prepared from example 8b using procedures described for examples 8c and9a; step 1) with methoxyacetyl chloride.

Example 112-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethy]-1,2,3,4-tetrahydroisoquinoline Dihydrochloride

A solution of 140 mg of(3,4-dihydro-1H-isoquinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanonein 6 mL of dry tetrahydrofuran was treated with 4 mL of 1Mborane-tetrahydrofuran complex in tetrahydrofuran and stirred under anatmosphere of nitrogen at room temperature for 15 h. The mixture wasslowly treated with 5 mL of concentrated HCl and heated at 45° C. for 5h. The mixture was then cooled to room temperature and made alkaline bythe cautious addition of solid sodium bicarbonate. After diluting withwater, the mixture was washed twice with 30 mL portions of ethylacetate. The combined organic extracts were washed with 30 mL of brine,dried over magnesium sulfate, and evaporated to dryness. The residue waspurified on a flash silica gel column eluting with 10% acetone/hexanesolvent yielding 47 mg of the free base. The dihydrochloride salt wasprepared using 1M HCl in ether giving 49 mg of2-[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride, mp 236.4–241° C.

TABLE 6 Compounds prepared in Examples 10a–10d, and 11. MH+ observedExample Structure Name (° C.) (predicted) 10a

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylicacidcyclopropylmethylpropylamide 120.6–122.0 415 (415) 10b

(3,4-Dihydro-1H-isoquinolin-2-yl)-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,56,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-methanone 80.3–87.7 415(415) 10c

N-[2-Methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide226–228 327 (327) 10d

2-Methoxy-N-[2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]acetamide133.8–135.0 343 (343) 11

2-[2-Methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinedihydrochloride236.4–241.0 401 (401)

Example 12a7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

A mixture of 200 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one(Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of drytetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg ofdiethylazodicarboxylate. The mixture was placed under an atmosphere ofnitrogen and stirred at room temperature for 16 h. The solvent wasevaporated and the residue was purified by flash column chromatographyon silica gel using 15% ethyl acetate/hexane as solvent giving 84 mg of7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineas a colorless oil, ms m/z 390 (MH⁺).

Example 12b7-(2,4-Dichlorophenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineHydrochloride

Example 12b was prepared according to the procedure described in Example12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(2,4-dichlorophenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.

Example 12c7-(2-methyl-4-methoxyphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineHydrochloride

Example 12c was prepared according to the procedure described in Example12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(4-methoxy-2-methyl-phenyl)-2-methyl-1,2,4,5,6,7-hexahydro-pyrazolo[3,4-b]pyridin-3-one.

Example 12d

Dimethyl-{4-methyl-5-[2-methyl-3-(1-propylbutoxy)-2,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridin-7-yl]-pyridin-2-yl}-amine

Example 12c was prepared according to the procedure described in Example12a, except that7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-onewas replaced by7-(6-dimethylamino-4-methylpyridin-3-yl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.

TABLE 7 Compounds prepared in Examples 12a–12d. MH+ mp observed ExampleStructure Name (° C.) (predicted) 12a

7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineoil 390 (390) 12b

7-(2,4-Dichlorophenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridinehydrochlorideoil 396 (396) 12c

7-(4-Methoxy-2-methylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridineoil 372 (372) 12d

Dimethyl-{4-methyl-5-[2-methyl-3-(1-propylbutoxy)-2,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridin-7-yl]-pyridin-2-yl}-amineoil 386 (386)

Example 13a2-Methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

A mixture of 200 mg of3-bromo-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,124 mg of 2-trifluoromethylphenylboronic acid, and 14 mg oftetrakistriphenylphosphine palladium (0) in 2 mL of dioxane was treatedwith a solution of 210 mg of sodium carbonate in 2 mL of water. Themixture was placed under an atmosphere of argon and heated to 100° C.for 20 h. The mixture was cooled to room temperature, diluted with 20 mLof ethyl acetate, washed with 20 mL of 1 M HCl and 20mL of brine, driedover magnesium sulfate, and evaporated to dryness. The residue waspurified by flash silica gel column chromatography using 7%acetone/hexane as solvent yielding 87 mg of2-methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine,mp 59–63° C.

Example 13b3-(2,6-Dimethoxyphenyl)-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine

Example 13b was prepared according to the procedure described in Example13a, except that 2-trifluoromethylphenylboronic acid was replaced by2,6-bismethoxyphenylboronic acid.

TABLE 8 Compounds prepared in Examples 13a–13b. Example Structure Namemp (° C.) MH+ observed (predicted) 13a

2-Methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine59–63 400 (400) 13b

3-(2,6-Dimethoxyphenyl)-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine169.9–172.8 392 (392)

Example 14 Contemplated Compounds

In addition to the compounds exemplified herein, the compounds shown inTable 9 are contemplated to fall within the scope of the invention. Inaddition, the compounds shown in Table 9 illustrate certain species ofcompounds that are generically described herein.

TABLE 9 Contemplated compounds

Example 15 Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate  0.5%The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate  0.5%Crosscarmellose sodium  2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%The ingredients are combined and, granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 mlThe ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation (IV)

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to makeisotonic Water for injection to  100 mlThe active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

Ingredient % wt./wt. Active ingredient  1.0% Polyethylene glycol 100074.5% Polyethylene glycol 4000 24.5%The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation

Ingredients grams Active compound 0.2–2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025–0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50–100 microliters of formulation peractuation. A typical dosing schedule is 2–4 sprays every 4–12 hours.

Example 16 Intracellular cAMP Stimulation Assay

Human Y-79 retinoblastoma cells are grown in RPMI 1640 medium with 15%FBS. Measures of cAMP accumulation are performed by using NEN AdenylylCyclase FlashPlate kit (SMP004). The cells are separated from culturemedium, washed twice with PBS (150×g, 8 min), resuspended (2E+6cells/ml) in Stimulation Buffer (provided in the kit), and then added to96-well FlashPlates, (50,000 cells per well). Various concentrations oftest compounds are incubated with the cells for 20 min prior to theaddition of hCRF (30 nM). The total assay volume is 100 μl. The assay isterminated after 20 min after addition of the hCRF by addition ofDetection Buffer and [¹²⁵I]cAMP. After 2 hr at room temperature themixtures are aspirated and the bound radioactivity is measured with aPackard TopCount. The potency (IC₅₀ values) of test compounds ininhibiting the hCRF-stimulated accumulation of cAMP is determined bynonlinear regression analyses with interactive curve-fitting procedures.

Example 17 CRF Receptor Binding Assay

Human IMR-32 neuroblastoma cells are grown to 80% confluence in MEMmedium containing 10% heat-inactivated FBS, 1 mM Sodium Pyruvate, and0.1 mM nonessential amino acids. Celll membranes are prepared accordingthe method of Dieterich and DeSouza (1996). The cells (˜5E+9) areresuspended in 10 volumes of wash buffer (5 mM Tris HCl, 10 mM MgCl₂, 2mM EGTA, pH 7.4 at RT), homogenized with a Polytron, and thencentrifuged at 45,000 G for 20 min at 4° C. The membrane pellets arewashed twice with wash buffer (45,000 G for 20 min at 4° C.) and thenresuspended (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4 at RT).Protein concentration is determined using Pierce reagents and BSA asstandard. Aliquots of 1–1.5 ml are stored at −80° C. until bindingassay.

The competition binding assay is performed in a final volume of 250 μl,which contains assay buffer (50 mM Tris-HCl, 10 mM MgCl₂, 2 mM EGTA,0.2% BSA, 0.1 mM bacitracin and 100 klU/ml aprotinin pH 7.2 at R.T.),0.05 nM [¹²⁵I]Tyr⁰-ovine CRF (Du Pont New England Nuclear), 50 μg ofmembrane protein, and test compound at various concentrations.Non-specific binding is determined with 1 μM hCRF. Binding reactions areterminated after 2 hr incubation at 25° C. by filtering through 96-wGF/C filter plate using a Packard Harvester (Filtermate 196). The 96-wfilter plate is pre-treated with 0.3% polyethyleneimine and pre-washedwith washing buffer (50 mM Tris-HCl, 10 mM MgCl₂, 2 mM EGTA, 0.2% BSA,pH 7.2 at 4° C.). Unbound radioactivity is removed by four rapid washes(0.8 ml/well) with wash buffer. The radioactivity is quantified using aPackard TopCount. Data are analyzed using non-linear iterative curvefitting to obtain IC₅₀ and Hill slope values. PKi values are derivedfrom pIC₅₀ values (−log of IC₅₀).

The compounds of the present invention were active in the receptorbinding and functional assay. The IC₅₀ of of representative examples inthe CRF functional assay are shown in Table 10.

TABLE 10 CRF1 receptor binding affinity of compounds of Formula I.Example hCRF1 (pIC₅₀)  1 5.97  5c 4.95  6e 6.63  7b 7.06  9c 6.08 114.92 12b 7.56 13a 6.11

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, orprocess step or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of Formula I or Formula II:

wherein: R¹ is —NR^(a)R^(b); R² is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylalkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, aryl, orarylalkyl, wherein said aryl or arylalkyl is optionally substituted withone or more substituents independently selected from C₁₋₆alkyl,haloalkyl, C₁₋₆alkoxy, and halogen; R³ and R⁴ are each independentlyselected from hydrogen and C₁₋₆alkyl, or R³ and R⁴ are taken togetherwith the carbon to which they are attached to form a C₃₋₆cycloalkylring; Ar is aryl optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano,nitro, and —NR^(a″)R^(b″), where R^(a″) and R^(b″) are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,and C₁₋₆alkylcarbonyl; R^(a) is C₁₋₆alkyl, C₁₋₆alkoxyalkyl,C₁₋₆alkylthioalkyl; and R^(b) is heteroarylalkyl; n is 1; a is a singlebond; or individual isomers, racemic or non-racemic mixtures of isomers,or pharmaceutically acceptable salts thereof.
 2. The compound of claim1, wherein the compound is of Formula I:

and R¹ is —NR^(a)R^(b).
 3. The compound of claim 2, wherein Ar is a di-or tri-substituted phenyl, and the substituents are each independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and—NR^(a″)R^(b″), where R^(a″) and R^(b″) are each independently selectedfrom the group consisting of hydrogen, C₁₋₆alkyl, and C₁₋₆alkylcarbonyl.4. The compound of claim 3, wherein R³ and R⁴ are each independentlyselected from hydrogen and methyl.
 5. The compound of claim 4, whereinAr is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl.
 6. Thecompound of claim 5, wherein Ar is a 2,4-disubstituted or2,4,6-trisubstituted phenyl, and the substituents are each independentlyselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylthio, halogen, haloalkyl, cyano, alkylamino, dialkylamino, andnitro.
 7. The compound of claim 6, wherein R² is hydrogen, C₁₋₆alkyl, orC₁₋₆alkylcarbonyl.
 8. The compound of claim 7, wherein R³ and R⁴ areeach independently selected from hydrogen and methyl.
 9. The compound ofclaim 8, wherein R² is C₁₋₆alkyl; R³ and R⁴ are hydrogen; and Ar is a2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituentsare independently selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloalkyl, cyano, and —NR^(a″)R^(b″), where R^(a″)and R^(b″) are each independently selected from the group consisting ofhydrogen and C₁₋₆alkyl.
 10. A pharmaceutical composition comprising atherapeutically effective amount of at least one compound of claim 1 inadmixture with at least one pharmaceutically acceptable carrier.
 11. Themethod of treating a disease state selected from the group consisting ofphobias, stress-related illnesses, mood disorders, eating disorders,generalized anxiety disorders, stress-induced gastrointestinaldysfunctions, neurodegenerative diseases, and neuropsychiatric disorderscomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of claim 1.